A number of studies suggested that Treg exert their suppressive function on effector T cells indirectly by modifying the function of antigen-presenting
dendritic cells. Interestingly, a recent in vitro study showed that LFA-1 is important for the formation of dendritic cell/Treg aggregates, because LFA-1−/− Treg were no longer able to inhibit the maturation of cocultured dendritic cells 20. Similar effects were also observed in a mixed human/mouse suppression system 21. We Selleck CYC202 show here that LFA-1 deficiency results in a reduced Treg/effector cell ratio in the inflamed CNS. The reduction in Treg was already established in the spleen and thymi of unimmunized LFA-1−/− mice. Hence, besides a possible functional impairment of Dorsomorphin order Treg lacking LFA-1, these results indicate a more fundamental role for LFA-1 in generation of FoxP3+ Treg in the thymus. ICAM-1, a ligand of LFA-1, is expressed on thymic stromal cells 22. Therefore, LFA-1 potentially increases the
physical contact between thymocytes and stromal cells, resulting in enhanced T-cell receptor triggering. Increased T-cell receptor signaling during thymocyte selection favors the generation of naturally occurring Treg 23, which would explain the contribution of LFA-1 to the generation of naturally occurring Treg. So far, LFA-1 has been mainly recognized as a molecule regulating the migration of lymphocytes. Generally, the migration of LFA-1-deficient T cells to the peripheral lymph nodes is impaired, resulting in significantly smaller lymph nodes 10, 14. However, upon immunization with MOG-peptide, we observed that these differences in cellularity in lymph nodes between WT and LFA-1 KO mice are more or less levelled out (data not shown). In the context of EAE and transendothelial migration, Laschinger et al. 11 demonstrated that encephalitogenic G protein-coupled receptor kinase T cells do not use LFA-1 for the initial adhesion to the endothelium of the blood/brain barrier. Instead, LFA-1 was involved in the later phases of migration into the CNS parenchyma. However, it should be noted that these results were obtained for the healthy spinal cord and that the role of LFA-1 for migration
could be different during later stages of an EAE disease, in which other integrin interactions may compensate for the lack of LFA-1. In our study, we did not directly address the question of lymphocyte migration via the blood/brain barrier. However, the observation that the frequency of MOG reactive CD4+ T cells in LFA-1−/− mice is already higher outside the CNS suggests an impaired suppression of effector T cells by Treg rather than an altered migration as cause for the higher ratio of effector versus Treg in the inflamed CNS in LFA-1−/−. Overall, the exacerbated EAE in the absence of LFA-1 seems to be due to the impaired suppression of autoantigen-specific effector T cells by Treg, which in LFA-1−/− mice show a more extensive expansion in secondary lymphoid organs upon immunization with the MOG-peptide.